Despite impressive advances in the broad field of innate immunity, our understanding of host resistance to viral infection remains quite tentative. Few subjects in immunology are more important. Newly emergent viruses have the potential to kill hundreds of millions of people, and long-familiar viruses have repeatedly proven their ability to do so. The present Program Project proposal is intended to advance our understanding of host resistance to viruses at the most fundamental level. It has been written in light of our collective experience in the analysis of innate immunity. We believe that any attempt to decipher innate immunity must incorporate three elements. First, there must be evolutionary perspective. The innate immune system of all present day metazoans has been evolving for 800 million years or more, and key features of numerous defensive system have been conserved. The host defense function of the Toll pathway in Drosophila was recognized two years before independent efforts revealed the importance of homologous pathways in mammals. It is also widely known that the TNF signaling pathways of mammals are, in some measure, mimicked by a separate innate response pathway (Imd) in Drosophila. This proposal aims to accelerate discovery of the proteins that serve innate immunity based on the fact that ancestral functions are often conserved across a great evolutionary divide. Second, there must be a means to the rapid discovery of "new" proteins essential for host resistance (herein described as the resistome). Classical ("forward") genetics, which has enlightened virtually every aspect of biology, will be used for this purpose. Classical genetic analysis is particularly useful for the dissection of phenomena that are still poorly understood. It has been immensely empowered by recent advances in techniques for mapping and sequencing, and by elucidation of the mouse and Drosophila genomes. It often reveals functions that could never be grasped through hypothesis or through application of non-genetic discovery-oriented tools. Third, there must be a means of targeting specific genes and testing the effects of germline mutations. Gene targeting can quickly decipher the function of specific proteins where there is strong reason to believe that they participate in a biological process. Moreover, germline mutations are extremely reliable tools in the analysis of innate immunity: far more so than any other tools that we have at hand. Herein, we detail a plan for the analysis of inherited resistance to viral infection that enlists each of these three elements. Much remains to be learned about host resistance to viruses, and only recently have the essential sensing mechanisms by which the host detects viral infections begun to emerge. The present proposal will fill existing gaps in our knowledge about how viral infections are sensed, how their presence is communicated both within and among cells and tissues of the host, and how they can be efficiently eradicated.